Dr. Rawlings’ primary research interests include dysregulated B cell development and signaling leading to immunodeficiency, autoimmunity or lymphoid malignancies, and the development of gene therapy for primary immune deficiency diseases. The Rawlings laboratory uses expertise in basic and clinical immunology, signal transduction and lymphocyte developmental biology to understand how altered signals can lead to immunologic disease, with the ultimate goal of developing translational therapies capable of specifically modulating these disorders. Dr. Rawlings is a member of multiple regional and national organizations as well as of an NIH study section, chairman for the USIDNET XLA patient registry, and ad-hoc reviewer for various grant programs and immunology journals. He also co-directs the Northwest Genome Engineering Consortium, a research program funded as part of the NIH Roadmap for Medical Research and comprised of seven collaborative projects focused on developing enzymatic reagents and delivery methods for site-specific gene repair in hematopoietic stem cells. Dr. David Rawlings pursues three major research themes: (1) B cell antigen receptor (BCR) engagement generates a multi-component complex of signaling effectors, or "signalosome." Current studies seek to understand better the components and interactions that constitute the signalosome through genetic and biochemical analysis of tyrosine kinases, adapter proteins, and lipid enzymes; and the use of animal models to evaluate the developmental consequences of altered expression of these proteins. A major focus of this current work is the multi-adapter protein CARMA1, which plays a crucial role in development of human B cell lymphomas. This work includes structural studies in collaboration with Roland Strong. (2) Human and murine in vitro B lineage culture models are used in conjunction with animal-based approaches (transgenic, knockout, and lentiviral vector-based RNA interference) to model B cell lineage development and B lymphoid malignancies. Current studies include analysis of thymic stromal lymphopoeitin-receptor (TSLP), Toll, Notch, and BAFF-receptor signaling cascades in the generation of peripheral B cell subsets and the PKC?/NF?B pathways in the development or progression of lymphoma. The work with TSLP involves collaboration with Dr. Steven Ziegler. (3) Gene therapy has the potential to correct primary immunodeficiency disorders. Because of the selective advantage for gene corrected cells in affected hosts, X-linked agammaglobulinemia and Wiskott-Aldrich Syndrome represent excellent disease targets for stem cell-based gene therapy. In addition to the use of cell lineage-specific viral vectors systems, we have begun to evaluate the potential of employing homing endonucleases to facilitate genetic repair of the mutant loci in animal models, in collaboration with Dr. Andrew Scharenberg and Dr. Nancy Maizels.